In the next phase of this longstanding project, we will expand our work on the cross-sectional and longitudinal structural relationships among genetically based dimensions of temperament (e.g., neuroticism), environmentally based dimensions of lower-order vulnerability, and the DSM-IV anxiety and mood disorder constructs. Over 1,750 subjects will be assessed with a variety of interview and self-report measures of temperament, vulnerability, and emotional disorder and will provide a blood or saliva sample for genotyping analysis. These data will be submitted to structural equation modeling (SEM) analyses to address a variety of specific aims including: (a) the first comprehensive evaluation of Barlow's triple vulnerability theory of emotional disorders;and (b) the differential relationships of selected candidate genes (e.g., 5-HTTLPR, BDNF, COMT, TPH) with dimensions of temperament and DSM-IV psychopathology. Longitudinal SEM analyses will examine a number of specific aims including: (a) the influence of genotypes in explaining the longitudinal course of DSM-IV disorder constructs and dimensions of vulnerability;(b) the extent to which genotypes interact with psychosocial treatment and life stress (GxE) to account for the course of temperament and psychopathology;(c) a temporal examination of Barlow's triple vulnerability theory (e.g., temporal directional relationships between temperament and psychological vulnerability in explaining course of DSM-IV disorders);and (d) a fine-grained analysis of the (bi)directional influence of temperament and DSM-UV psychopathology during the course of psychosocial treatment. A series of psychometric studies (e.g., item response theory, factor mixture modeling) will be conducted to address questions bearing on the classification of disorders in DSM-V (e.g., utility of dimensional vs. categorical classification;empirically based disorder subtyping;invariance of criteria sets across demographic subgroups). Key contributions of this work include: comprehensive evaluation of leading conceptual models of emotional disorders;explication of genetic factors that influence the severity and course of DMS-IV disorders, and refinement of the DSM-IV disorder and associated constructs that will inform DSM-V as well as biological studies by suggesting a more valid and robust set of disorder and vulnerability constructs on which to base such investigations.